Children. Children (0–13 years) were excluded from the Nix-TB study; therefore, no analysis specific to this subgroup of patients could have been performed. It is recommended that children with pulmonary MDR/RR-TB with additional resistance to fluoroquinolones be given the same consideration for longer treatment regimens as adults, to include components with a safety profile that is better established. Bedaquiline is currently only recommended for children aged 6 years and above.¹⁸ Additional data on the use of BPaL in children, when eligible, would be useful, and this may be a feature of carefully planned and monitored operational research studies or clinical trials.
PLHIV. PLHIV represented half of those enrolled in the Nix-TB study. However, it was impossible to perform any adjusted stratified analyses for PLHIV, due to the sample size. PLHIV were eligible to enrol in the Nix-TB study if they had a CD4 count of more than 50 cells/uL and if they were using permitted antiretroviral medications.¹⁹ In the operational research context, clinicians or investigators may consider and decide on the eligibility criteria for enrolment, which may be different from the Nix-TB study regarding CD4 count. It is important to note drug–drug interactions when administering TB and HIV medications in combination, including the documented interactions between bedaquiline and efavirenz. There are two important drug–drug interactions between antiretroviral drugs and bedaquiline, also mentioned above: efavirenz induces metabolism of bedaquiline – its co-administration with bedaquiline may result in reduced bedaquiline exposure and loss of activity, and it is therefore not recommended; and ritonavir may increase bedaquiline exposure, which could potentially increase the risk of bedaquiline-related adverse reactions, so the combination of bedaquiline with ritonavir should be avoided or be administered with caution (see Table 6.2) (52–54). ART regimens should be modified to avoid these drugs for an HIV-positive patient treated with a BPaL regimen. Efavirenz also reduces pretomanid exposures significantly; therefore, an alternative antiretroviral agent should be considered if pretomanid or the BPaL regimen is to be used (96). Regimens including zidovudine should be used with special caution because both zidovudine and linezolid may cause peripheral nerve toxicity and are known to have myelosuppression cross-toxicity.
Pregnant and lactating women were excluded from the Nix-TB study; therefore, no analysis specific to this subgroup of patients could be performed, and safety of the BPaL regimen in pregnant and lactating women has not been established. In such cases, it is recommended that a longer regimen be individualized to include components with a safety profile that is better established. The safety of pretomanid in pregnant and lactating women has not been established. The use of bedaquiline in pregnancy has been shown to be associated with infants born with a lower mean birth weight than infants whose mothers did not take bedaquiline; however, this did not appear to be a clinically significant finding when infants were followed over time. Breastfeeding is not recommended for women taking BPaL.
Extrapulmonary TB. Patients with extrapulmonary TB were excluded from the Nix-TB study. Therefore, the WHO recommendations for longer MDR-TB regimens apply to patients with extrapulmonary disease, including for those with TB meningitis. There are few data on the CNS penetration of bedaquiline or pretomanid.
Patients with very limited treatment options. In some instances, patients will have extensive drugresistance profiles that may make it difficult (or impossible) to construct a regimen based on existing recommendations. In such situations, the patient’s life may be endangered. Therefore, for individual patients for whom it is not possible to design an effective regimen based on existing recommendations, the BPaL regimen may be considered as a last resort under prevailing ethical standards.
¹⁷ Overall, 18 (17.3%) patients in the Nix-TB study (n=109) completed a full course of linezolid at the 1200 mg dose, 38 (36.5%) completed with a 600 mg dose, 16 (15.4%) completed with a 300 mg dose and 32 (30.7%) stopped linezolid early due to an adverse event. Additional studies are underway to assess the optimal dosing and duration of linezolid for the treatment of drug-resistant TB.
¹⁸ Based on the results of an RCT conducted by the manufacturer, the US FDA has extended approval for the use of bedaquiline for children aged 5 years and above (32). However, these data have not yet been assessed by WHO.
¹⁹ These permitted antiretroviral treatments were: nevirapine in combination with any nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir in combination with any NRTIs; tenofovir/lamivudine/abacavir (if normal renal function); triple NRTI therapy comprising zidovudine, lamivudine and abacavir (noting the increased risk of peripheral nerve toxicity with zidovudine and linezolid), and raltegravir in combination with NRTIs.